Thank you so much for your kind supports in Kaohsiung Medical University (KMU) in Taiwan for over 16 years (2009 to 2026). After conceiving my performances in KMU, I regret myself several points which I am not able to attain my initial plan. During this period, the movement of anti-Japan was invading into our districts, even in Southern part of Taiwan and the coronavirus Disease 2019 (COVID-19). The letter events infected more than 33 million people worldwide and led to more than 1 million deaths until 2020, Oct. We have a tight situation for locking out Kaohsiung. During these periods, I also cannot achieve any research performance in my area during my stay in Taiwan. In addition, I noticed that the researchers in KMU were closed and highly competitive even though such a smallest society. Thus, I cannot change such a solid style of the politics. I am afraid of such a characteristic of the people in KMU. In addition, I cannot grow up the young researchers in KMU inside. This might be my reflection although I enjoyed the foreign life here. During 16 years, I cannot attain my minimum contribution to the Science in KMU. This is a reason of my reflection. In strictly, several friends in Academia SINICA, Taiwan and in Japan told me that I am not good enough because I cannot publish the papers like Nature Communication or NATURE sister journals or SCIENCE/CELL sister journals. My publications have been cited more than 10,000 times, with an h-index exceeding 55, and more than 150 papers were cited more than 10 times = i10-index >150 [Clarivate’s Highly Cited Researchers (HCR) list] (This index did not include the papers from 1976 to 1996, about 60 papers). These main performances are due to the research activities in RIKEN, Japan, not in Taiwan. Thus, it is true. My friends and young students in Japan and some friends in Taiwan performed the research as over 100-300 h-index. Thus, I regret why I cannot publish or even send the papers to the reasonable journals in Taiwan. This is a big criticism to me. Thus, I regret my life to stay here. I am so sorry about this accomplishment. However, I am happy to teach a lot of young professors and students in KMU. In addition, I learned a lot about the consciousness of people on Southern Taiwan in historical and their kindness. Indeed, I was educated many different life styles in Taiwan by many people. When I came here, I was very happy to attend the KMU Jornal club which were organized by the young PI and clinicians within many different departments. This is a good memory for me, indeed. I am so happy to have an opportunity to discuss with them. Now they grew up and became the independent professors. Therefore, thank you so much for your kindness. I also thank you for other supporting my research life and educations. Over 16 years— a good memory!! But still I am not satisfied with my performance in Kaohsiung. This is a big reflection during my stay for over 16 years.

Preface

Over the past quarter-century, the fields of molecular oncology and transcriptional regulation have been transformed by a wave of discoveries that have redefined our understanding of chromatin dynamics, cellular reprogramming, epigenetic plasticity, and cancer evolution. Among the scientists whose contributions shaped this transformation, Dr. Kazushige Yokoyama occupies a unique position. His body of work—spanning transcription factor biology, histone acetylation, viral gene therapy platforms, stem cell–derived organoids, and ligand-responsive signaling networks—reflects a rare integration of mechanistic precision and translational ambition. This book is an attempt to bring these diverse yet interconnected contributions together into a single, coherent narrative.

Before the emergence of modern epigenetics and chromatin biology, Dr. Yokoyama made pioneering contributions to transcriptional regulation through the first successful application of Antisense RNA technology to block the c-Myc proto-oncogene. These landmark studies provided the earliest experimental evidence that antisense RNA could selectively repress endogenous oncogene expression, establishing a conceptual and methodological foundation for antisense-based therapeutic strategies in cancer and viral infection. This early body of work positioned nucleic acid–mediated gene silencing as a viable regulatory mechanism well before antisense approaches entered broader biomedical development.

Intricately linked to this early phase of his career were the first mechanistic studies demonstrating how Adenovirus type 12 E1A induces controlled expression of Major histocompatibility complex (MHC) class I genes. Dr. Yokoyama's work elucidated how viral gene products regulate host antigen presentation through defined promoter elements and transcriptional control, providing foundational insight into virus–host interactions, immune modulation, and oncogenic transformation. These discoveries established a critical conceptual bridge between viral transcriptional regulation, immune surveillance, and later developments in oncolytic virotherapy.

The chapters in this volume follow a chronological–conceptual arc that mirrors the trajectory of Dr. Yokoyama's research. The early chapters examine pioneering efforts in histone acetylation, highlighting the surprising discovery that transcription factors such as ATF-2 and CIITA possess intrinsic acetyltransferase functions. This foundational insight reshaped how scientists view transcriptional coactivators and chromatin-modifying enzymes. These investigations revealed that the epigenetic machinery is not confined to canonical HATs and HDACs but extends to transcription factors themselves, which can directly modify chromatin structure.

From chromatin regulation, the narrative moves toward Dr. Yokoyama's innovative work in oncolytic virotherapy, where conditionally replicative adenoviruses were engineered to target biliary tract and gallbladder cancers with remarkable specificity. The development of the Virus BANK system further demonstrated the group's commitment to building scalable and versatile viral delivery platforms that could serve both basic biomedical research and therapeutic innovation.

The middle portion of the book explores the expanding influence of the transcription factor JDP2, a recurring focus of Dr. Yokoyama's publications. JDP2 emerged as a central regulator of histone acetylation, nucleosome remodeling, cell cycle progression, oxidative stress response, immune homeostasis, and neural and cerebellar development. These findings positioned JDP2 not merely as a transcriptional repressor but as a dynamic coordinator of cellular identity and stress adaptation. Several groundbreaking studies document how JDP2 interfaces with ROS signaling, the Nrf2/MafK axis, apoptosis resistance, osteoclast differentiation, and stem cell biology—revealing a unifying theme across tissues and disease states.

The chapters that follow turn toward cancer stemness, epithelial–mesenchymal transition (EMT), and tumor progression, focusing on the transcriptional networks that govern these processes. Discoveries such as the OCT4–c-JUN feedback loop, the SPZ1–TWIST oncogenic axis, and BRD4-mediated epigenetic reprogramming not only deepen our mechanistic understanding of metastasis but also uncover new therapeutic entry points in liver and gastric cancers. These studies bridge molecular oncology with regenerative biology by demonstrating that reprogramming pathways, initially associated with pluripotent stem cells, can be hijacked by tumors to promote aggressiveness.

The later chapters examine one of the most innovative aspects of Dr. Yokoyama's recent research: the use of three-dimensional organoids and iPSC-derived systems to study microbial oncogenesis, tumor heterogeneity, drug resistance, and inflammation. This includes seminal work on Helicobacter pylori-induced signaling, phase II enzyme ligands, HDGF/TNF-α crosstalk, and lineage reprogramming in cerebellar progenitors. These models represent a shift from traditional cell line-based experiments to complex systems that better mimic the microenvironment and cellular diversity of human tissues.

The book culminates with an exploration of the AHR–NRF2–JDP2 gene battery, a signaling architecture that integrates environmental ligands, oxidative stress, and transcriptional control. These chapters highlight a sophisticated regulatory network with broad therapeutic implications—from cancer immunology to toxicology, metabolism, and regenerative medicine.

Throughout this volume, a consistent theme emerges: the power of transcriptional regulation as both a molecular compass and a therapeutic lever. Dr. Yokoyama's work demonstrates that understanding how transcription factors and epigenetic modifiers communicate, recruit cofactors, and remodel chromatin can reveal deep insights into disease mechanisms and expose vulnerabilities that might otherwise remain hidden.

This volume is written not only for scientists who follow these fields closely but also for clinicians, students, and interdisciplinary researchers seeking an integrated perspective on how transcriptional control shapes cancer biology, stem cell dynamics, inflammation, and cellular identity. The book does not attempt to review every related publication exhaustively but instead aims to provide a structured synthesis anchored in the most influential discoveries from Dr. Yokoyama's research portfolio.

We hope that this work serves as a bridge—connecting past breakthroughs with emerging frontiers—and inspires new generations of scientists to explore the elegant complexity of gene regulation, epigenetic plasticity, and cancer evolution.

Dr. Kazunari K. Yokoyama is an internationally distinguished molecular biologist whose career spans more than five decades of groundbreaking research. Born in Hokkaido, Japan, in 1951, he has dedicated his scientific life to advancing global understanding of transcriptional regulation, chromatin biology, oxidative stress signaling, stem cell reprogramming, and cancer development.

Dr. Yokoyama completed his B.A. at Shizuoka University (1973), followed by an M.S. (1976) and a Ph.D. (1979) from the University of Tokyo, Department of Science, Division of Biophysical and Biochemical Chemistry. His doctoral and early research training under Professors Kazutomo Imahori and Toshiaki Osawa laid the foundation for a lifetime of innovation across molecular biology, immunology, and genetics.

After earning his doctorate, Dr. Yokoyama conducted postdoctoral research at the Albert Einstein College of Medicine (1979–1983) under Dr. Stanley Nathenson, where he made significant contributions to the molecular structure of MHC class I genes and immune regulation. He was also instructed by Dr. Lloyd J. Old in Memorial Sloan Kettering Cancer Research Center in New York, to teach the TL antigen for cancer therapy. Then, he continued his advanced research at the Beckman Research Institute of the City of Hope (1983–1985) and later at RIKEN's Tsukuba Life Science Center (1985–2000), where he ultimately served as Head of the DNA Bank and then Head of the Gene Engineering Division within the BioResource Center (2001–2009). He was selected as the international exchange-scholar between RIKEN (Japan) and Pasteur Institute (France) (1991), and the short-term cooperative researcher by Academia Sinica (Taiwan) (2010).

His career includes prestigious international collaborations, including an exchange research position at the Pasteur Institute in France and visiting professorships or lectureships at numerous universities and institutes in Japan, China, and the United States. These include the University of Tokyo, Hiroshima University, Kagoshima University, Tokushima University, the Shanghai Institute of Biochemistry and Cell Biology (SIBCB, CAS), Fudan University, the Second Military Medical University, China Medical University, and the University of Tennessee Medical School.

In 2009, Dr. Yokoyama joined Kaohsiung Medical University (KMU) in Taiwan, where he served as Professor in the Cancer Center, Environmental Medicine, Stem Cell Center, and Infectious Diseases and Cancer Center. Since 2021, he has been a Medical Researcher and Professor at the Cell Therapy and Research Center, Kaohsiung Medical University Hospital, and a Visiting Professor at the Graduate Institute of Medicine at KMU.

Dr. Yokoyama has authored more than 300 scientific papers in English and over 60 publications in Japanese. His work appears in top-tier journals including Nature, Science, Nature Genetics, Molecular Cell, Genes & Development, Nature Structural and Molecular Biology, EMBO Journal, Immunity, and PNAS. These publications helped establish him as a global authority in transcriptional regulation, AP-1/JDP2 biology, virotherapy, cancer stem cell regulation, oxidative stress, and organoid-based cancer modeling.

Over the course of his career, he has received numerous honors from institutions including China Medical University, Fudan University, the Secondary Military Medical University, and the Shanghai Biotechnology Association. Dr. Yokoyama is a member of major scientific societies, including the American Association for Cancer Research, the American Society for Microbiology, the New York Academy of Sciences, and the International Society for Stem Cell Research. He also serves as an editor or associate editor for several respected journals, including Stem Cell Research and Therapy, Cancers, International Journal of Molecular Sciences, and eBioMedicine.

Dr. Yokoyama has an extensive record of scientific service, acting as a reviewer for national and international grant agencies, including the Human Frontier Science Program, the European Commission, and multiple scientific ministries across Japan, Israel, Italy, Australia, and the United States.

His primary research contributions span several major fields:

1. Molecular biology of the AP-1 repressor JDP2 in oxidative stress and antioxidant defense

2. Stem cell biology, drug development, and reprogramming technology3.

3. Cancer stem cell biology, especially in liver and gastric cancers

4. Virotherapy and gene therapy using engineered viruses5.

5. Organoid-based cancer modeling using iPSCs

Across his long and distinguished career, Dr. Kazunari K. Yokoyama has remained committed to exploring the fundamental molecular mechanisms that govern cellular identity, defense, reprogramming, and oncogenesis. His pioneering contributions continue to influence modern biomedical research and inspire new generations of scientists around the world.

　

I wish someone like young professors will make an effort to rebuild the education system in Taiwan and Kaohsiung Medical University.

在台灣的生活經歷使我認知到台灣教育體系中存在的問題，尤其是醫學教育，並提醒我可以如何解決這些問題，為了發展台灣的創造力及培育具獨特性的學生，迫切需要加深與亞洲各國的合作及培育台灣的獨特性教育。個人建議與其他大學或研究所合作，種下希望的種子能夠發芽成長，期待將來台灣的學術形態能有根本上的改變。具有這種潛力的年輕一代正在成長。最後在此感謝你們，個人已經準備就緒繼續再耕耘半年。

在邁入75歲人生之時，作為轉換跑道之紀念！